Carcinogenesis is the result of the deregulation of the fundamental biological processes involved in cell growth and differentiation. Two proteins, p53 and MDM2, appear to play reciprocal roles in regulating the cellular progression toward tumorigenicity.
p53, a tumor suppressor gene, acts as a transcription factor and negatively regulates cell growth by controlling entry into the cell cycle. Mutations in this gene are found in over 60% of all cancers. p53 acts to protect the cell after DNA damage by activating the transcription of target genes which initiate cell cycle arrest until the damage can be repaired. Alterations in the sequence, expression, subcellular localization, or concentration of the p53 protein product can result in the tumor phenotype (Momand and Zambetti, J. Cell. Biochem., 1997, 64, 343-352).
In contrast to the cell survival properties of p53, a protein called MDM2, acts in the opposite manner producing an oncogenic phenotype when overexpressed. MDM2 promotes cellular growth by directly binding to p53 thereby sequestering the protein and thus inactivating its tumor suppressor function (Momand and Zambetti, J. Cell. Biochem., 1997, 64, 343-352).
Recently, another p53-associating protein was isolated in mice and based on its structural similarity to MDM2 was called MDMX (Shvarts et al., Embo J., 1996, 15, 5349-5357). The human homolog has been reported and shares the same p53-associated features as the murine protein (Shvarts et al., Genomics, 1997, 43, 34-42).
MDMX (also known as mdm2-like p53 binding protein) was shown to bind to p53 in vivo and inhibit the trascription activation function of wild type p53. However, unlike MDM2, MDMX is not regulated in a p53-dependent manner. The MDMX transcript was found to be expressed in all human tissues with the highest levels found in the thymus and the lowest in the colon. By fluorescence in situ hybridization (FISH) analysis, MDMX was localized to chromosome 1q32, a region of the genome found to be amplified in several liposarcomas, possibly implicating MDMX in carcinogenesis (Shvarts et al., Genomics, 1997, 43, 34-42).
The nucleic acid sequence of the mouse MDMX gene is disclosed in WO96/41875 (Van Der Eb et al., 1996, ). Also disclosed in WO96/41875 is a vector containing the DNA, transformants containing this vector and methods of producing MDMX with this vector. In addition, this PCT application discloses methods of screening for substances which may bind p53 using the MDMX vector in hybridization assays.
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of MDMX. Consequently, there remains a long felt need for additional agents capable of effectively inhibiting MDMX function.
It is anticipated that antisense oligonucleotides against MDMX may therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications for the effective and specific modulation of MDMX expression.